Neurodegenerative diseases, neurovascular diseases and traumatic brain and spinal cord injuries are one of the most important causes of disability and death in the population. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke stand out among these diseases.
These diseases are generally characterized by a loss of neurons, which translates into the onset of language and memory disorders in Alzheimer's disease, movement coordination disorders in Parkinson's disease, paralysis of the voluntary muscles involved in motility, speech and respiration in amyotrophic lateral sclerosis (ALS), hemiplegias and sensory losses in stroke and paralysis in traumatic brain and spinal cord injuries.
Oxidative cell stress is involved in various neurodegenerative and neurovascular diseases. The central nervous system, and specifically the brain, has a high oxygen requirement. Oxygen consumption leads to the overproduction of so-called reactive oxygen species (ROS), such as superoxide or hydroxyl type free radicals or non-radical oxygen such as hydrogen peroxide (H2O2), which cause damage both in neuronal and in vascular cells (Oxidative neurotoxicity in rat cerebral cortex neurons: synergistic effects of H2O2 and NO on apoptosis involving activation of p38 mitogen-activated protein kinase and caspase-3, J. Y. Wang et al., J. Neurosci. Res. 72, 508-519 (2003)). To control the levels of these oxidant compounds, cells have antioxidant systems, such as superoxide dismutase, glutathione peroxidase, transferrin or vitamin E. Under normal physiological conditions there is an equilibrium between these antioxidant systems and reactive oxygen species. However, problems may arise when said equilibrium is altered due to a decrease of the antioxidant defenses and/or to an overproduction of reactive oxygen species. Under those conditions, oxidative stress can cause cell damage and subsequent cell death, neurons being particularly vulnerable cells.
It is known that oxidative stress is one of the main cell death mechanisms in different cytotoxic models, such as that of glutamate (Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection, H. Parfenova et al., Am. J. Physiol. 290: C1399-C1410 (2006)) or in the H2O2-induced cytotoxicity model (Distinct protective mechanisms of HO-1 and HO-2 against hydroperoxide-induced cytotoxicity, Y. S. Kim et al., Free Radic. Biol. Med. 38, 85-92 (2005)) and in neurodegenerative and neurovascular diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke and arteriosclerosis (Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview, E. Mariani et al., J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 827, 65-75 (2005); Oxidative stress and neuronal death/survival signaling in cerebral ischemia, A. Saito et al., Mol. Neurobiol. 31, 105-116 (2005); Oxidative stress in the context of acute cerebrovascular stroke, M. M. H. El Kossi et al., Stroke 31, 1889-1892 (2000); The oxidant stress hypothesis of atherogenesis, L. Iuliano, Lipids 36, suppl: S41-44 (2001)).
The compounds of the present invention are disaccharides containing one or more sulphate groups in their structure, first described in patent EP 1300411 (U.S. Pat. No. 6,680,304). They are useful in the treatment of arthrosis (patent EP 1300411) and in the treatment of tendon, ligament and bone diseases (patent application WO 2008/151898).
The basic structure of these compounds contains the monosaccharides glucuronic acid and glucosamine, bonded by means of β-(1→3) bonds, and with a sulphate group in C-4 and/or in C-6 of the monosaccharide glucosamine.
In view of the above, it is of great interest to find drugs capable of protecting neurons under oxidative stress conditions and of reducing the generation of reactive oxygen species. Said drugs could be highly useful as therapeutic tools for the treatment of neurodegenerative and/or neurovascular diseases, as well as for the treatment of traumatic brain or spinal cord injuries.
The use of the sulphated disaccharides of the present invention in the treatment of a neurodegenerative disease and/or of a neurovascular disease as well as in the treatment of a traumatic brain or spinal cord injury has not been described up until now.